After more than 20 years, scientists have solved the full-length
structure of a Janus Kinase

Date:
March 10, 2022
Source:
Howard Hughes Medical Institute
Summary:
More than two decades of effort went into a project that has now
revealed the structure of a crucial signaling molecule, opening
the door to new and better drugs for some cancers.



FULL STORY ==========================================================================
For more than 20 years, his team and others around the world had been
chasing an elusive quarry -- the 3D structure of a crucial signaling
protein in cells.

In late 2021, his electron microscope images of the molecule started to
come into focus. On December 8, postdoc Naotaka Tsutsumi and graduate
student Caleb Glassman sent him an email with a startlingly clear
picture of the protein latched on to a key receptor. "I was sitting in
a meeting, and I realized we had it," recalls Garcia, a Howard Hughes
Medical Institute Investigator at Stanford University. "I immediately
left the meeting and ran back to the lab."

========================================================================== Glassman, who had just moved to Boston for a Harvard postdoc, canceled
his planned backcountry trip, and rushed back to Stanford. "I wanted
to finish what Naotaka and I had started," he explains. Then the three researchers worked around the clock to nail the complete structure of
the protein, known as a Janus kinase, and beat competing labs to the
discovery. "It was a big horse race between many great groups worldwide,
and we were sprinting towards the finish line," Garcia says. On December
26, they rushed a manuscript to the journal Science, which published
the work on March 10, 2022.

Garcia's team has nabbed not just the full structure of a vitally
important signaling molecule, but also the mechanism for how these
kinases work, which had been "a fundamental question in biology," says
John O'Shea, an immunologist at the National Institutes of Health who
helped to develop one of the first drugs to block Janus kinase function
and was not involved with the new research. Because the proteins can go
awry in disease, the results could lead to new and better drugs against
certain cancers. "It's amazing work," O'Shea says.

Chipping away Janus kinases are one of the communication whizzes of the
animal kingdom. They take signals that come from outside cells and pass
the info along to molecules inside. Scientists have known for years
that malfunctioning Janus kinases can cause disease. Some mutations
that impair Janus kinases can severely curtail the body's ability to
fight off infection, causing a condition virtually identical to "bubble
boy disease." And when genetic glitches and exaggerated signals rev up
the kinases too much, the result can be blood cancers like leukemia,
and allergic or autoimmune diseases.

Researchers knew the shape of parts of the proteins, including related
enzyme and regulatory regions at the end of the molecule, which earned
them the name Janus kinases, after the two-faced mythological Roman
god. And sophisticated drug screens have unearthed molecules that inhibit
these proteins, giving doctors a way to treat some cancers and disorders
like rheumatoid arthritis.

But scientists developed the drugs without knowing the molecules' full structure or how they become activated. So most of the current arsenal of nearly a dozen drugs, plus more in clinical trials, are relatively blunt instruments, blocking both healthy and mutated Janus kinases. They can
still treat many diseases, from eczema to COVID-19, but also can cause
a range of side effects.



========================================================================== Garcia wanted a more detailed view of the proteins but, as he learned
when he first tried to image the molecules as a postdoc in 1995, it was
a daunting challenge. The kinases are notoriously difficult to make in
the lab. And they don't easily form crystals, which scientists need to
capture 3D structures using x-ray crystallography. So, for many years,
Garcia and others could only view bits of the kinases at a time. "We
kept chipping away without much to show for it," he says.

In the last few years, the pieces began to fall into place. One key
advance was a method called cryo-EM, where scientists freeze samples and
then view them using an electron microscope. Another was the choice by
Garcia's team to study a mouse Janus kinase rather than a less stable
human one. They also introduced a common cancer-causing mutation into
the mouse kinase, which stabilized the molecule even further.

Lighting a fire Garcia's team's work reveals the structure of a Janus
kinase called JAK1 and outlines the steps it uses to sends signals
within cells.

First, receptor proteins stud cell membranes, poking from the inner and
outer surfaces of the cell like a toothpick through a sandwich. Then, a
single Janus kinase inside the cell attaches to the receptors, waiting for
a signal. Next, molecules called cytokines approach the cell's exterior,
each binding to two receptors. The cytokines act like a bridge that
pulls the two receptors even closer, Garcia explains. That brings the
active ends of the Janus kinase together, switching them on. Like a
match lighting a fire, the kinase relays a signal that tells genes to
turn on or off.

The structure also reveals how the cancer-causing mutation short-circuits
this messaging chain -- by gluing two parts of the Janus kinase
together. That causes the two active regions to stay switched on even
when there are no outside cytokines, sparking uncontrolled activity that
can trigger cancers.

Garcia hopes the new results could help scientists design better drugs
that target only defective Janus kinases, allowing healthy versions to
keep performing their normal duties. The work, he says, is an example
of an "ideal situation in science, where solving a basic problem also
has direct relevance for disease."

========================================================================== Story Source: Materials provided by Howard_Hughes_Medical_Institute. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
* Janus_kinase_protein ========================================================================== Journal Reference:
1. Caleb R. Glassman, Naotaka Tsutsumi, Robert A. Saxton, Patrick J.

Lupardus, Kevin M. Jude, K. Christopher Garcia. Structure of
a Janus kinase cytokine receptor complex reveals the basis for
dimeric activation. Science, 2022; DOI: 10.1126/science.abn8933 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220310143650.htm

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